ALENDRONIC ACID APOTEX ONCE WEEKLY 70 MG TABLETS

Main information

  • Trade name:
  • ALENDRONIC ACID APOTEX ONCE WEEKLY 70 MG TABLETS
  • Dosage:
  • 70 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALENDRONIC ACID APOTEX ONCE WEEKLY 70 MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1513/004/001
  • Authorization date:
  • 24-04-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AlendronicAcidApotexOnceWeekly70mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains70mgalendronicacid(assodiumalendronate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

White,ovalbiconvextablet,engraved“APO”ononesideand“ALE70”ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpostmenopausalosteoporosis.AlendronicAcidApotexOnceWeekly70mgTabletsreducetheriskof

vertebralandhipfractures.

4.2Posologyandmethodofadministration

Fororaladministration.

Therecommendeddosageisone70mgtabletonceweekly.

Topermitadequateabsorptionofalendronate:

AlendronicAcidApotexOnceWeekly70mgTabletsmustbetakenatleast30minutesbeforethefirstfood,beverage,

ormedicinalproductofthedaywithplainwateronly.Otherbeverages(includingmineralwater),foodandsome

medicinalproductsarelikelytoreducetheabsorptionofalendronate(see4.5'Interactionwithothermedicinalproducts

andotherformsofinteraction').

Tofacilitatedeliverytothestomachandthusreducethepotentialforlocalandoesophagealirritation/adverse

experiences(see4.4'Specialwarningsandprecautionsforuse'):

AlendronicAcidApotexOnceWeekly70mgTabletsshouldonlybeswalloweduponarisingforthedaywitha

fullglassofwater(notlessthan200mlor7fl.oz.).

Patientsshouldnotchewthetabletorallowthetablettodissolveintheirmouthsbecauseofapotentialfor

oropharyngealulceration.

Patientsshouldnotliedownuntilaftertheirfirstfoodofthedaywhichshouldbeatleast30minutesaftertaking

thetablet.

Patientsshouldnotliedownforatleast30minutesaftertakingAlendronicAcidApotexOnceWeekly70mg

Tablets.

AlendronicAcidApotexOnceWeekly70mgTabletsshouldnotbetakenatbedtimeorbeforearisingfortheday.

PatientsshouldreceivesupplementalcalciumandvitaminDifdietaryintakeisinadequate(see4.4'Specialwarnings

andprecautionsforuse').

Useintheelderly:

Inclinicalstudiestherewasnoage-relateddifferenceintheefficacyorsafetyprofilesofalendronate.Thereforeno

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Useinrenalimpairment:

NodosageadjustmentisnecessaryforpatientswithGFRgreaterthan35ml/min.AlendronicAcidApotexOnce

Weekly70mgTabletsarenotrecommendedforpatientswithrenalimpairmentwhereGFRislessthan35ml/min,due

tolackofexperience.

Useinchildren(under18years):

Alendronatehasbeenstudiedinasmallnumberofpatientswithosteogenesisimperfectaunder18yearsofage.Results

areinsufficienttosupportitsuseinchildren.

AlendronicAcidApotexOnceWeekly70mgTabletshavenotbeeninvestigatedinthetreatmentofglucocorticoid-

inducedosteoporosis.

Theoptimaldurationofbisphosphonatetreatmentforosteoporosishasnotbeenestablished.Theneedforcontinued

treatmentshouldbere-evaluatedperiodicallybasedonthebenefitsandpotentialrisksofAlendronicAcidApotexOnce

Weekly70mgTabletsonanindividualpatientbasis,particularlyafter5ormoreyearsofuse.

4.3Contraindications

Abnormalitiesoftheoesophagusandotherfactorswhichdelayoesophagealemptyingsuchasstrictureor

achalasia.

Inabilitytostandorsituprightforatleast30minutes.

Hypersensitivitytoalendronateortoanyoftheexcipients.

Hypocalcaemia.

Seealso4.4'Specialwarningsandprecautionsforuse'.

4.4Specialwarningsandprecautionsforuse

Alendronatecancauselocalirritationoftheuppergastro-intestinalmucosa.Becausethereisapotentialforworsening

oftheunderlyingdisease,cautionshouldbeusedwhenalendronateisgiventopatientswithactiveuppergastro-

intestinalproblems,suchasdysphagia,oesophagealdisease,gastritis,duodenitis,ulcers,orwitharecenthistory

(withinthepreviousyear)ofmajorgastro-intestinaldiseasesuchaspepticulcer,oractivegastro-intestinalbleeding,or

surgeryoftheuppergastro-intestinaltractotherthanpyloroplasty(see4.3'Contra-indications').Inpatientswithknown

Barrett'soesophagus,prescribersshouldconsiderthebenefitsandpotentialrisksofalendronateonanindividualpatient

basis.

Oesophagealreactions(sometimessevereandrequiringhospitalisation),suchasoesophagitis,oesophagealulcersand

oesophagealerosions,rarelyfollowedbyoesophagealstricture,havebeenreportedinpatientsreceivingalendronate.

Physiciansshouldthereforebealerttoanysignsorsymptomssignallingapossibleoesophagealreactionandpatients

shouldbeinstructedtodiscontinuealendronateandseekmedicalattentioniftheydevelopsymptomsofoesophageal

irritationsuchasdysphagia,painonswallowingorretrosternalpain,neworworseningheartburn.

Theriskofsevereoesophagealadverseexperiencesappearstobegreaterinpatientswhofailtotakealendronate

properlyand/orwhocontinuetotakealendronateafterdevelopingsymptomssuggestiveofoesophagealirritation.Itis

veryimportantthatthefulldosinginstructionsareprovidedto,andunderstoodbythepatient(see4.2'Posologyand

methodofadministration').Patientsshouldbeinformedthatfailuretofollowtheseinstructionsmayincreasetheirrisk

ofoesophagealproblems.

Whilenoincreasedriskwasobservedinextensiveclinicaltrials,therehavebeenrare(post-marketing)reportsof

gastricandduodenalulcers,somesevereandwithcomplications.Acausalrelationshipcannotberuledout.

PatientsshouldbeinstructedthatiftheymissadoseofAlendronicAcidApotexOnceWeekly70mgTablets,they

shouldtakeonetabletonthemorningaftertheyremember.Theyshouldnottaketwotabletsonthesamedaybut

shouldreturntotakingonetabletonceaweek,asoriginallyscheduledontheirchosenday.

AlendronateisnotrecommendedforpatientswithrenalimpairmentwhereGFRislessthan35ml/min,(see4.2

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Causesofosteoporosisotherthanoestrogendeficiencyandageingshouldbeconsidered.

Hypocalcaemiamustbecorrectedbeforeinitiatingtherapywithalendronate(see4.3'Contra-indications').Other

disordersaffectingmineralmetabolism(suchasvitaminDdeficiencyandhypoparathyroidism)shouldalsobe

effectivelytreated.Inpatientswiththeseconditions,serumcalciumandsymptomsofhypocalcaemiashouldbe

monitoredduringtherapywithAlendronicAcidApotexOnceWeekly70mgTablets

Duetopositiveeffectsofalendronateinincreasingbonemineral,decreasesinserumcalciumandphosphatemay

occur.Theseareusuallysmallandasymptomatic.However,therehavebeenreportsofsymptomatichypocalcaemia,

whichoccasionallyhavebeensevereandoftenoccurredinpatientswithpredisposingconditions(e.g.

hypoparathyroidism,vitaminDdeficiencyandcalciummalabsorption).EnsuringadequatecalciumandvitaminD

intakeisthereforeparticularlyimportantinpatientsreceivingglucocorticoids.

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimensincludingprimarilyintravenouslyadministered

biphosphonates.Manyofthesepatientswerealsoreceivingchemotherapywithcorticosteroids.Osteonecrosisofthe

jawhasalsobeenreportedinpatientswithosteoporosisreceivingoralbiphosponates.

Adentalexaminationwithappropriatepreventivedentistryshouldbeconsideredpriortotreatmentwith

biphosphonatesinpatientswithconcomitantriskfactors(e.g.cancer,chemotherapy,radiotherapy,corticosteroids,poor

oralhygieneperiodontaldisease).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbiphosphonatetherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbiphosphonatetreatment

reducestheriskofosteonecrosisinthejaw.

Clinicaljudgementofthetreatingphysicianshouldguidethemanagementplanofeachpatientbasedonindividual

benefit/riskassessment.

Bone,joint,and/ormusclepainhasbeenreportedinpatientstakingbisphosphonates.Inpost-marketingexperience,

thesesymptomshaverarelybeensevereand/orincapacitating(see‘4.8Undesirableeffects’).Thetimetoonset

symptomsvariedfromonedaytoseveralmonthsafterstartingtreatment.Mostpatientshadreliefofsymptomsafter

stopping.Asubsethadrecurrenceofsymptomswhenrechallengedwiththesamedrugoranotherbisphosphonate.

Atypicalfracturesofthefemur:

Atypicalsubtrochantericanddiaphysealfemoralfractureshavebeenreportedwithbisphosphonatetherapy,primarily

inpatientsreceivinglong-termtreatmentforosteoporosis.Thesetransverseorshortoblique,fracturescanoccur

anywherealongthefemurfromjustbelowthelessertrochantertojustabovethesupracondylarflare.Thesefractures

occurafterminimalornotraumaandsomepatientsexperiencethighorgroinpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fracturesareoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureshasalsobeenreported.Discontinuationofbisphosphonate

therapyinpatientssuspectedtohaveanatypicalfemurfractureshouldbeconsideredpendingevaluationofthepatient,

basedonanindividualbenefitriskassessment.

Duringbisphosphonatetreatmentpatientsshouldbeadvisedtoreportanythigh,hiporgroinpainandanypatient

presentingwithsuchsymptomsshouldbeevaluatedforanincompletefemurfracture.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Iftakenatthesametime,itislikelythatfoodandbeverages(includingmineralwater),calciumsupplements,antacids,

andsomeoralmedicinalproductswillinterferewithabsorptionofalendronate.Therefore,patientsmustwaitatleast30

minutesaftertakingalendronatebeforetakinganyotheroralmedicinalproduct(see4.2'Posologyandmethodof

administration'and5.2'Pharmacokineticproperties').

Nootherinteractionswithmedicinalproductsofclinicalsignificanceareanticipated.Anumberofpatientsinthe

clinicaltrialsreceivedoestrogen(intravaginal,transdermal,ororal)whiletakingalendronate.Noadverseexperiences

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Althoughspecificinteractionstudieswerenotperformed,inclinicalstudiesalendronatewasusedconcomitantlywitha

widerangeofcommonlyprescribedmedicinalproductswithoutevidenceofclinicaladverseinteractions.

4.6Fertility,pregnancyandlactation

Useduringpregnancy:

Therearenoadequatedatafromtheuseofalendronateinpregnantwomen.Animalstudiesdonotindicatedirect

harmfuleffectswithrespecttopregnancy,embryonal/foetaldevelopment,orpostnataldevelopment.Alendronategiven

duringpregnancyinratscauseddystociarelatedtohypocalcemia(see5.3'Preclinicalsafetydata').Giventhe

indication,alendronateshouldnotbeusedduringpregnancy.

Useduringlactation:

Itisnotknownwhetheralendronateisexcretedintohumanbreastmilk.Giventheindication,alendronateshouldnotbe

usedbybreast-feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Notrelevant.

4.8Undesirableeffects

Inaone-yearstudyinpost-menopausalwomenwithosteoporosistheoverallsafetyprofilesofAlendronateSodium

OnceWeekly70mg(n=519)andalendronate10mg/day(n=370)weresimilar.Intwothree-yearstudiesofvirtually

identicaldesign,inpost-menopausalwomen(alendronate10mg:n=196,placebo:n=397)theoverallsafetyprofilesof

alendronate10mg/dayandplaceboweresimilar.Adverseexperiencesreportedbytheinvestigatorsaspossibly,

probablyordefinitelydrug-relatedarepresentedbelowiftheyoccurredin1%ineithertreatmentgroupintheone-

yearstudy,orin 1%ofpatientstreatedwithalendronate10mg/dayandatagreaterincidencethaninpatientsgiven

placebointhethree-yearstudies:

One-YearStudy Three-YearStudies

Alendronate

OnceWeekly

70mg

(n=519)

Alendronate

10mg/day

(n=370)

Alendronate

10mg/day

(n=196)

Placebo

(n=397)

Gastro-intestinal

abdominalpain 3.7 3.0 6.6 4.8

dyspepsia 2.7 2.2 3.6 3.5

acidregurgitation 1.9 2.4 2.0 4.3

nausea 1.9 2.4 3.6 4.0

abdominaldistention 1.0 1.4 1.0 0.8

constipation 0.8 1.6 3.1 1.8

diarrhoea 0.6 0.5 3.1 1.8

dysphagia 0.4 0.5 1.0 0.0

flatulence 0.4 1.6 2.6 0.5

gastritis 0.2 1.1 0.5 1.3

gastriculcer 0.0 1.1 0.0 0.0

oesophagealulcer 0.0 0.0 1.5 0.0

Musculoskeletal

musculoskeletal(bone,

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Thefollowingadverseexperienceshavealsobeenreportedduringclinicalstudiesand/orpost-marketinguseand

rankedunderthefollowingfrequency:

Verycommon:(1/10)

Common: (1/100to<1/10)

Uncommon: (1/1,000to<1/100)

Rare: (1/10,000to<1/1,000)

Veryrare: (<1/10,000),

notknown(cannotbeestimatedfromtheavailabledata).

Immunesystemdisorders:

Rare:hypersensitivityreactionsincludingurticariaandangioedema.

Metabolismandnutritiondisorders:

Rare: Symptomatichypocalcaemia,ofteninassociationwithpredisposingconditions(see4.4'Specialwarningsand

precautionsforuse').

Nervoussystemdisorders:

Common:headache.

Eyedisorders:

Rare:uveitis,scleritis,episcleritis.

Gastrointestinaldisorders:

Common:abdominalpain,dyspepsia,constipation,diarrhoea,flatulence,oesophagealulcer*,dysphagia*,abdominal

distension,acidregurgitation.

Uncommon:nausea,vomiting,gastritis,oesophagitis*,esophagealerosions*,melaena.

Rare:oesophagealstricture*,oropharyngealulceration*,uppergastrointestinalPUBsperforation,ulcers,bleeding),

althoughacausalrelationshipcannotberuledout.

Skinandsubcutaneoustissuedisorders:

Uncommon:rash,pruritus,erythema.

Rare:rashwithphotosensitivity.

Veryrareandisolatedcases:severeskinreactions,includingStevens-Johnsonsyndromeandtoxicepidermal

necrolysishavebeenreported.

Musculoskeletal,connectivetissueandbonedisorders:

Common:musculoskeletal(bone,muscleorjoint)pain.

Rare:Osteonecrosisofthejawhasbeenreportedinpatientstreatedbybiphosphonates.Themajorityofthereports

refertocancerpatients,butsuchcaseshavealsobeenreportedinpatientstreatedforosteoporosis.Osteonecrosis

ofthejawisgenerallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis).Diagnosis

ofcancer,chemotherapy,radiotherapy,corticosteroidsandpoororalhygienearealsodeemedasriskfactors;

severemusculoskeletal(bone,muscleorjoint)pain(seesection4.4).

Generaldisordersandadministrationsiteconditions:

Rare:transientsymptomsasinanacute-phaseresponse(myalgia,malaiseandrarely,fever),typicallyinassociation

withinitiationoftreatment.

musclecramp 0.2 1.1 0.0 1.0

Neurological

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Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyrare):

Musculoskeletal,connectivetissueandbonedisorders:Atypicalsubtrochantericand

diaphysealfemoralfractures(bisphosphonateclassadversereaction)

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencynotknown):

Nervoussystemdisorders: dizziness

Earandlabyrinthdisorders: vertigo

Skinandsubcutaneoustissuedisorders: alopecia

Musculoskeletal,connectivetissueandbonedisorders: jointswelling

Generaldisordersandadministrationsiteconditions:asthenia,peripheraloedema

Laboratorytestfindings:

Inclinicalstudies,asymptomatic,mildandtransientdecreasesinserumcalciumandphosphatewereobservedin

approximately18and10%,respectively,ofpatientstakingalendronate10mg/dayversusapproximately12and3%of

thosetakingplacebo.However,theincidencesofdecreasesinserumcalciumto<8.0mg/dl(2.0mmol/l)andserum

phosphateto 2.0mg/dl(0.65mmol/l)weresimilarinbothtreatmentgroups.

4.9Overdose

Hypocalcaemia,hypophosphataemiaanduppergastro-intestinaladverseevents,suchasupsetstomach,heartburn,

oesophagitis,gastritis,orulcer,mayresultfromoraloverdosage.Nospecificinformationisavailableonthetreatment

ofoverdosagewithalendronate.Milkorantacidsshouldbegiventobindalendronate.Owingtotheriskofoesophageal

irritation,vomitingshouldnotbeinducedandthepatientshouldremainfullyupright.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Bisphosphonate,forthetreatmentofbonediseases.

ATCcode:M05BA04

Theactiveingredientalendronicacid(assodiumalendronate),isabisphosphonatethatinhibitsosteoclasticbone

resorptionwithnodirecteffectonboneformation.Preclinicalstudieshaveshownpreferentiallocalisationof

alendronatetositesofactiveresorption.Activityofosteoclastsisinhibited,butrecruitmentorattachmentofosteoclasts

isnotaffected.Theboneformedduringtreatmentwithalendronateisofnormalquality.

Treatmentofpost-menopausalosteoporosis

OsteoporosisisdefinedasBMDofthespineorhip2.5SDbelowthemeanvalueofanormalyoungpopulation

orasapreviousfragilityfracture,irrespectiveofBMD.

ThetherapeuticequivalenceofAlendronateSodiumOnceWeekly70mg(n=519)andalendronate10mgdaily(n=370)

wasdemonstratedinaone-yearmulticentrestudyofpost-menopausalwomenwithosteoporosis.Themeanincreases

frombaselineinlumbarspineBMDatoneyearwere5.1%(95%CI:4.8,5.4%)inthe70mgonce-weeklygroupand

5.4%(95%CI:5.0,5.8%)inthe10mgdailygroup.ThemeanBMDincreaseswere2.3%and2.9%atthefemoralneck

and2.9%and3.1%atthetotalhipinthe70mgonceweeklyand10mgdailygroups,respectively.Thetwotreatment

groupswerealsosimilarwithregardtoBMDincreasesatotherskeletalsites.

Theeffectsofalendronateonbonemassandfractureincidenceinpost-menopausalwomenwereexaminedintwo

initialefficacystudiesofidenticaldesign(n=994)aswellasintheFractureInterventionTrial(FIT:n=6,459).

Intheinitialefficacystudies,themeanbonemineraldensity(BMD)increaseswithalendronate10mg/dayrelativeto

placeboatthreeyearswere8.8%,5.9%and7.8%atthespine,femoralneckandtrochanter,respectively.Totalbody

BMDalsoincreasedsignificantly.Therewasa48%reduction(alendronate3.2%vsplacebo6.2%)intheproportionof

patientstreatedwithalendronateexperiencingoneormorevertebralfracturesrelativetothosetreatedwithplacebo.In

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neckandtotalbodyweremaintained.

FITconsistedoftwoplacebo-controlledstudiesusingalendronatedaily(5mgdailyfortwoyearsand10mgdailyfor

eitheroneortwoadditionalyears):

FIT1:Athree-yearstudyof2,027patientswhohadatleastonebaselinevertebral(compression)fracture.Inthis

studyalendronatedailyreducedtheincidenceof 1newvertebralfractureby47%(alendronate7.9%vs.

placebo15.0%).Inaddition,astatisticallysignificantreductionwasfoundintheincidenceofhip

fractures(1.1%vs.2.2%,areductionof51%).

FIT2:Afour-yearstudyof4,432patientswithlowbonemassbutwithoutabaselinevertebralfracture.Inthis

study,asignificantdifferencewasobservedintheanalysisofthesubgroupofosteoporoticwomen(37%

oftheglobalpopulationwhocorrespondwiththeabovedefinitionofosteoporosis)intheincidenceofhip

fractures(alendronate1.0%vs.placebo2.2%,areductionof56%)andintheincidenceof 1vertebral

fracture(2.9%vs.5.8%,areductionof50%).

5.2Pharmacokineticproperties

Absorption:

Relativetoanintravenousreferencedose,theoralmeanbioavailabilityofalendronateinwomenwas0.64%fordoses

rangingfrom5to70mgwhenadministeredafteranovernightfastandtwohoursbeforeastandardisedbreakfast.

Bioavailabilitywasdecreasedsimilarlytoanestimated0.46%and0.39%whenalendronatewasadministeredonehour

orhalfanhourbeforeastandardisedbreakfast.Inosteoporosisstudies,alendronatewaseffectivewhenadministeredat

least30minutesbeforethefirstfoodorbeverageoftheday.

Bioavailabilitywasnegligiblewhetheralendronatewasadministeredwith,oruptotwohoursafter,astandardised

breakfast.Concomitantadministrationofalendronatewithcoffeeororangejuicereducedbioavailabilityby

approximately60%.

Inhealthysubjects,oralprednisone(20mgthreetimesdailyforfivedays)didnotproduceaclinicallymeaningful

changeinoralbioavailabilityofalendronate(ameanincreaserangingfrom20%to44%).

Distribution:

Studiesinratsshowthatalendronatetransientlydistributestosofttissuesfollowing1mg/kgintravenousadministration

butisthenrapidlyredistributedtoboneorexcretedintheurine.Themeansteady-statevolumeofdistribution,

exclusiveofbone,isatleast28litresinhumans.Concentrationsofdruginplasmafollowingtherapeuticoraldosesare

toolowforanalyticaldetection(<5ng/ml).Proteinbindinginhumanplasmaisapproximately78%.

Biotransformation:

Thereisnoevidencethatalendronateismetabolisedinanimalsorhumans.

Elimination:

Followingasingleintravenousdoseof[ 14

C]alendronate,approximately50%oftheradioactivitywasexcretedinthe

urinewithin72hoursandlittleornoradioactivitywasrecoveredinthefaeces.Followingasingle10mgintravenous

dose,therenalclearanceofalendronatewas71ml/min,andsystemicclearancedidnotexceed200ml/min.Plasma

concentrationsfellbymorethan95%withinsixhoursfollowingintravenousadministration.Theterminalhalf-lifein

humansisestimatedtoexceedtenyears,reflectingreleaseofalendronatefromtheskeleton.Alendronateisnot

excretedthroughtheacidicorbasictransportsystemsofthekidneyinrats,andthusitisnotanticipatedtointerfere

withtheexcretionofothermedicinalproductsbythosesystemsinhumans.

Characteristicsinpatients:

Preclinicalstudiesshowthatthedrugthatisnotdepositedinboneisrapidlyexcretedintheurine.Noevidenceof

saturationofboneuptakewasfoundafterchronicdosingwithcumulativeintravenousdosesupto35mg/kginanimals.

Althoughnoclinicalinformationisavailable,itislikelythat,asinanimals,eliminationofalendronateviathekidney

willbereducedinpatientswithimpairedrenalfunction.Therefore,somewhatgreateraccumulationofalendronatein

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5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityandcarcinogenicpotential.Studiesinratshaveshownthattreatmentwithalendronate

duringpregnancywasassociatedwithdystociaindamsduringparturitionwhichwasrelatedtohypocalcaemia.In

studies,ratsgivenhighdosesshowedanincreasedincidenceofincompletefoetalossification.Therelevancetohumans

isunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Magnesiumstearate

Mannitol

Microcrystallinecellulose(PH102)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

ClearPVC/PVDC/Alblisterscontaining2or4tablets.

Packsizes:2,4,8,12,40tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ApotexEuropeB.V.

Darwinweg20

2333CRLeiden

Netherlands

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:24thApril2009

Dateoflastrenewal:12thAugust2011

10DATEOFREVISIONOFTHETEXT

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